Glutamate receptors are involved in excitatory synaptic transmission throughout the brain, and play important roles in neuronal circuits responsible for leaning and the establishment of synaptic connections during development, as well as epileptogenesis and ischemic neuron injury. Our long-term-goal is to identify and then manipulate the glutamate receptor subtypes involved in epileptogenesis and ischemic brain damage. We focus on the GluR2 subunit since it appears to control the calcium permeability of recombinant AMPA receptors. We have designed complementary molecular biological and electrophysiological approaches to compare the properties and function of native glutamate receptors in hippocampal interneurons that either lack or include the GluR2 subunit. Our major goals include: l. To clearly determine whether the presence of the GluR2 subunit limits calcium permeability of native AMPA receptors in individual hippocampal interneurons. 2. To identify arthropod toxins that are specific antagonists of calcium-permeable AMPA receptors, and to use these toxins to explore the synaptic physiology of this receptor subtype in the hippocampus. 3. To determine whether the GluR2 subunit lags the other AMPA receptor subunits in development in hippocampal interneurons, and the functional consequences of this developmental pattern. 4. To explore the forms of NMDA receptor-independent plasticity experienced by hippocampal interneurons that involve calcium influx through AMPA receptors lacking the GluR2 subunit. These experiments will clarify the roles of the GluR2 subunit in native AMPA receptors. Since drugs that prevent excessive calcium influx through non-NMDA glutamate receptors may have considerable therapeutic value, such information may lead to improved treatment for the brain damage associated with stroke and epilepsy.